Diabetes, Obesity and Metabolism 16: 739–747, 2014. © 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Pharmacodynamics of the glucagon-like peptide-1 receptor agonist lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus poorly controlled on sulphonylureas with/without metformin Y. Seino1 , A. Takami2 , G. Boka3 , E. Niemoeller4 & D. Raccah5 on behalf of the PDY6797 investigators 1 Kansai Electric Power Hospital, Osaka, Japan 2 Sanofi K.K., Tokyo, Japan 3 Sanofi, Chilly Mazarin, France 4 Sanofi, Frankfurt, Germany 5 University Hospital Sainte-Marguerite, Marseille, France
Aims: The PDY6797 study evaluated efficacy, safety and pharmacodynamics of lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus (T2DM) insufficiently controlled with sulphonylureas with/without metformin.
Methods: This randomized, double-blind, placebo-controlled trial comprised a single-dose assessment of lixisenatide 5 and 10 μg, and a 5to 6-week repeated dose-escalation assessment of lixisenatide 5 to 30 μg once (QD) or twice daily (BID). The primary endpoint was change in postprandial plasma glucose (PPG) area under the curve (AUC)[0:29–4:30 h] after a standardized breakfast at the highest tolerated lixisenatide dose. Change from baseline in glycated haemoglobin (HbA1c), 2-h PPG and fasting plasma glucose (FPG) were assessed, as were adverse events. Results: Change from baseline in PPG AUC[0:29–4:30 h] with lixisenatide QD and BID was significantly greater than placebo (p < 0.0001 for all study populations), with particularly prominent effects in Japanese patients. Greater reductions in PPG AUC[0:29–4:30 h] were seen with lixisenatide QD versus BID, while the totality of evidence suggested that the lixisenatide 20 μg dose was optimal. In the overall population, changes from baseline for 2-h PPG, HbA1c and FPG were significant with lixisenatide QD and BID versus placebo (p < 0.01 for all). Lixisenatide was well tolerated. Conclusions: Lixisenatide significantly reduced PPG AUC[0:29–4:30 h] versus placebo at the highest well-tolerated dose in patients with T2DM treated with sulphonylureas with/without metformin and had a good safety and tolerability profile. Japanese patients experienced particular benefits with lixisenatide in terms of reductions in PPG excursions. Keywords: Caucasian, Japanese, lixisenatide, prandial, type 2 diabetes mellitus Date submitted 5 November 2013; date of first decision 12 December 2013; date of final acceptance 6 February 2014
Introduction Type 2 diabetes mellitus (T2DM) is a metabolic disorder that occurs as a result of insulin resistance and low levels of endogenous insulin production regardless of ethnicity. However, the characteristics of glucoregulation differ between Japanese and Caucasian individuals with or without T2DM. For example, Japanese persons reportedly have decreased early-phase insulin secretion, lower levels of β-cell function, a decreased reserve capacity of insulin secretion and increased insulin resistance compared with normative levels based on Caucasian Correspondence to: Yutaka Seino, MD, PhD, Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima Ku, Osaka 553-0003, Japan. E-mail:
[email protected] This is an open access article under the terms of the Creative Commons AttributionNonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
populations [1–3]. Furthermore, in Japanese populations, a high frequency of a number of polymorphisms in genes with roles in normal glucose homeostasis and energy expenditure has been reported, predisposing some individuals to obesity [4,5]. In spite of a metabolic background of low insulin secretion, the traditional Japanese lifestyle has historically had a protective effect against diabetes. However, the encroachment of sedentary work and a Western high-fat diet has increased insulin resistance in many Japanese individuals, which, in combination with predisposing genetic and metabolic factors, has resulted in a sudden upsurge in the prevalence of T2DM. Indeed, more than 13% of the Japanese population now has either T2DM or impaired glucose tolerance [6]. In individuals with normal glycaemic control, the release of insulin is amplified by the incretin hormones, limiting the extent of postprandial plasma glucose (PPG) excursions [7,8]. The incretin glucagon-like peptide-1 (GLP-1) is released postprandially by the intestine, leading to the release of insulin
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Figure 1. Trial design at the 5 μg starting dose for lixisenatide or volume-matched placebo in patient cohort 1. Patients in cohort 2 received a single injection of lixisenatide 10 μg at randomization. Patients in cohort 2 started treatment with the 10 μg dose and then followed the same dose increase regimen, meaning that they received treatment for 1 week less than patients in cohort 1.
and the suppression of glucagon release. Native GLP-1 is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4) [9]. Endogenous GLP-1 levels are low in healthy Japanese subjects and in Japanese patients with T2DM; furthermore, mealinduced secretion of GLP-1 is considered to be negligible in both of these groups [10–12]. Early T2DM can generally be controlled with lifestyle measures and the use of oral antidiabetic drugs (OADs) [13,14]. Sulphonylureas have historically been, and continue to be, the most commonly used OAD in Japan; however, use of other OADs, including the biguanide metformin, is growing [15]. T2DM is a chronic disease and increasing insulin resistance and declining β-cell function may mean that add-on medication to OADs is required to maintain effective glycaemic control. Lixisenatide (Lyxumia®; Sanofi, Paris, France) is a oncedaily (QD) prandial GLP-1 receptor agonist (RA) for the treatment of T2DM. Lixisenatide is structurally similar to the GLP-1 RA exenatide and both are structurally related to, but distinct from, GLP-1 and withstand degradation by DPP-4, thus prolonging their activity at GLP-1 receptors [16]. Compared with exenatide, lixisenatide has a modified C terminus. This trial evaluated the pharmacodynamics of lixisenatide in Japanese and Caucasian patients with T2DM poorly controlled on sulphonylureas with or without metformin in order to provide data pertaining to potential effects of ethnicity, and also efficacy and safety data with dose escalation. A stepwise dose initiation with lixisenatide was further evaluated in the phase
740 Seino et al.
III clinical programme in order to minimize gastrointestinal adverse events (AEs), which are a class effect with GLP1 RAs. The effects of GLP-1 RAs as monotherapies or in combination with insulin or OADs in Asian patients and, more specifically, Japanese patients have been investigated previously [17–27]. However, the possibility that low endogenous GLP-1 production in Japanese patients results in differential effects with GLP-1 RA treatment compared with effects in Caucasian patients is intriguing and a direct comparison trial has not been reported previously. The PDY6797 trial comprised a single-dose assessment of lixisenatide 5 and 10 μg, and a 5- to 6-week repeated doseescalation assessment of lixisenatide once (QD) or twice daily (BID) following dose increases from 5 to 30 μg. In both sets of assessments, the effect of lixisenatide was monitored on PPG excursions after a standardized breakfast.
Materials and Methods Trial Design This was an international, multicentre, randomized, doubleblind, placebo-controlled, combined single-dose and repeated dose-escalation, parallel-group trial conducted in Japanese and Caucasian patients. The trial was conducted at 30 centres in five countries (Australia, Germany, Japan, South Africa and the Netherlands). The trial comprised five periods (Figure 1): (i) an up to 2-week screening phase; (ii) a single-blind placebo
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run-in period of 1 week with volume-matched placebo for lixisenatide 5 μg BID (i.e. one injection in the morning before breakfast and one injection in the evening before dinner); (iii) a single-dose period with randomization on the first day of dosing with a single injection in the morning (lixisenatide 5 μg or volume-matched placebo in cohort 1 and lixisenatide 10 μg or volume-matched placebo in cohort 2), followed by a placebo injection observation period of 2 days; (iv) a double-blind, placebo-controlled, dose-escalation, parallel-group period of 5 or 6 weeks of repeated-dose treatment administered QD or BID (according to starting dose: i.e. lixisenatide 10 μg per injection or volume-matched placebo, or 5 μg per injection or volume-matched placebo); and (v) a posttreatment follow-up period of 72 ± 24 h. All patients signed an informed consent form. The protocol for this trial complied with the recommendations of the Declaration of Helsinki and was submitted to and approved by independent ethics committees and/or the institutional review boards for each of the participating centres. Patients were centrally randomized by an interactive voice response system in a 1 : 1 : 1 ratio to receive lixisenatide BID, lixisenatide QD or matching placebo within each ethnicity. The trial was double-blind with regard to QD/BID regimen and active versus placebo treatment but was not blinded with regard to trial drug volume. A central laboratory was used for the analysis of efficacy and safety parameters in this study (BARC, Ghent, Belgium) and an independent Data Monitoring Committee supervised the conduct of the study. Possible allergic events were adjudicated in a blinded manner by an external Allergic Reaction Assessment Committee (ARAC). Study Population. Included patients were Japanese or Caucasian men and postmenopausal women aged 20–75 years at screening with T2DM for at least 1 year prior to screening diagnosed according to American Diabetes Association criteria [28]. All included patients had glycated haemoglobin (HbA1c) ≥7.0 and ≤10.0% at the time of screening. Japanese patients living outside Japan were required to have Japanese nationality, both parents Japanese, and have not lived outside Japan for >5 years. Treatment with sulphonylurea with/without metformin was required to be at a stable dose for at least 3 months prior to screening. At the time of screening, included patients had a body mass index (BMI) ≤35 kg/m2 at screening and fasting plasma glucose (FPG) between 108 and 250 mg/dl (6.0–13.9 mmol/l). The main exclusion criteria were use of OADs other than a sulphonylurea or metformin within 3 months prior to screening or use of insulin for ≥1 week within the 6 months before screening. Other exclusion criteria included a history of chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease or irritable bowel syndrome, or a clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including gastroparesis, within 6 months prior to the time of screening. Interventions. Lixisenatide or volume-matched placebo were self-administered subcutaneously in the thigh, abdomen or upper arm using a pen-type injector (OptiClik®, Sanofi). During the single-dose assessment, patients were administered
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original article the investigational drug (lixisenatide or volume-matched placebo) 5 μg (cohort 1) or 10 μg (cohort 2) exactly 30 min before the standardized meal. In the repeated dose-escalation assessment, patients in cohort 1 administered a starting dose of 5 μg QD or BID increasing every week in 5 μg increments – provided safety and tolerability did not prevent further dose increase – up to a total of 30 μg daily in the QD group and 60 μg daily in the BID group for 6 weeks. Patients in cohort 2 started with a dose of 10 μg QD or BID and then followed the same dose increase regimen described for cohort 1. Patients receiving lixisenatide QD administered lixisenatide in the morning and placebo in the evening; patients receiving lixisenatide BID administered lixisenatide in the morning and evening. Patients continued their previous dosage of sulphonylurea with/without metformin at a stable dose throughout the trial. Efficacy and Safety Assessments. The primary endpoint of this trial was change from baseline in PPG area under the curve (AUC)[0:29–4:30 h] (h · mg/dl) after a standardized breakfast on the last day at the highest well-tolerated dose. This parameter was considered to be appropriate in light of the 5- or 6-week study duration, the available evidence with lixisenatide and the mechanism of action of GLP-1 RAs. Ingredients of the standardized 500 kcal breakfast were orange juice (180 ml), toasted bread (60 g), jam or preserves (20 g), butter or margarine (10 g), whole milk (120 ml), and coffee or tea with non-nutritive sweetener if desired [29]. Secondary endpoints included the treatment by ethnicity interaction of increasing QD/BID doses of lixisenatide on PPG AUC[0:29–4:30 h] (h · mg/dl) after a standardized breakfast in Japanese and Caucasian patients and change from baseline in PPG AUC[0:29–4:30 h] and 2-h PPG (mg/dl) after a standardized breakfast on the last day of lixisenatide 10, 20 and 30 μg doses or on the last day at the highest well-tolerated dose. Additional secondary endpoints were: change from baseline in FPG (mg/dl), HbA1c (%) and body weight on the last day of treatment at the highest well-tolerated dose. AEs were monitored, including injection-site reactions, vital signs (blood pressure and heart rate), 12-lead electrocardiograms, laboratory tests (haematology and serum chemistry), symptomatic hypoglycaemia and severe hypoglycaemia. Symptomatic hypoglycaemia was defined as symptoms consistent with hypoglycaemia with an accompanying blood glucose
